UCSF

Myelin is the insulating membrane concentrically wrapped around some axons, which serves to increase the speed and efficiency of action potential propagation. In the central nervous system (CNS), myelin is formed by oligodendrocytes, which differentiate from self-renewing oligodendrocyte precursor cells (OPCs) throughout life. While factors intrinsic to oligodendrocyte lineage cells control certain features of myelination, extrinsic cues also play an important role in regulating myelination both in development and in response to experience. Thus far, identifying these extrinsic molecular players has proved challenging. Chapter 1 of this thesis describes the known patterns of CNS myelination and provides a framework to understand how neuronal signaling could influence this architecture, using it to evaluate previous work in this field. Chapter 2 presents our experimental work identifying one of these extrinsic neuronal cues for myelination as the neuropeptide dynorphin. We demonstrate that dynorphin, which is released from neurons upon high levels of activity, promotes experience-dependent myelination. Following forced swim stress, an experience that induces striatal dynorphin release, we observe increased striatal OPC differentiation and myelination, which is abolished by deleting dynorphin or blocking its endogenous receptor, kappa opioid receptor (KOR). We find dynorphin also promotes developmental OPC differentiation and myelination, and demonstrate that this effect requires KOR expression specifically on OPCs. We characterize dynorphin-expressing neurons and use genetic sparse-labeling to trace their axonal projections. Surprisingly, we find they are unmyelinated normally and following forced swim stress, in part due to their small size. We propose a new model whereby experience-dependent and developmental myelination is mediated by unmyelinated, neuropeptide-expressing neurons that promote OPC differentiation for the myelination of neighboring axons. Chapter 3 evaluates our findings in the context of the framework presented in Chapter 1 and comments on the significance of our work.